Bitterlings are carp-like teleost fish (Cypriniformes: Acheilanathidae) known for their specialized brood parasitic lifestyle. Bitterling embryos, in fact, develop inside the gill chamber of their... Show moreBitterlings are carp-like teleost fish (Cypriniformes: Acheilanathidae) known for their specialized brood parasitic lifestyle. Bitterling embryos, in fact, develop inside the gill chamber of their freshwater mussel hosts. However, little is known about how their parasitic lifestyle affects brain development in comparison to nonparasitic species. Here, we document the development of the brain of the rosy bitterling, Rhodeus ocellatus, at four embryonic stages of 165, 185, 210, 235 hours postfertilization (hpf) using micro-computed tomography (microCT). Focusing on developmental regionalization and brain ventricular organization, we relate the development of the brain divisions to those described for zebrafish using the prosomeric model as a reference paradigm. Segmentation and three-dimensional visualization of the ventricular system allowed us to identify changes in the longitudinal brain axis as a result of cephalic flexure during development. The results show that during early embryonic and larval development, histological differentiation, tissue boundaries, periventricular proliferation zones, and ventricular spaces are all detectable by microCT. The results of this study visualized with differential CT profiles are broadly consistent with comparable histological studies, and with the genoarchitecture of teleosts like the zebrafish. Compared to the zebrafish, our study identifies distinct developmental heterochronies in the rosy bitterling, such as a precocious development of the inferior lobe. Show less
Sclerosteosis is a rare bone dysplasia characterized by greatly increased bone mass, especially of the long bones and the skull. Patients are tall, show facial asymmetry and often have syndactyly.... Show moreSclerosteosis is a rare bone dysplasia characterized by greatly increased bone mass, especially of the long bones and the skull. Patients are tall, show facial asymmetry and often have syndactyly. Clinical complications are due to entrapment of cranial nerves. The disease is thought to be due to loss-of-function mutations in the SOST gene. The SOST gene product, sclerostin, is secreted by osteocytes and transported to the bone surface where it inhibits osteoblastic bone formation by antagonizing Wnt signaling. In a small Turkish family with sclerosteosis, we identified a missense mutation (c.499T>C; p.Cys167Arg) in exon 2 of the SOST gene. This type of mutation has not been previously reported and using different functional approaches, we show that it has a devastating effect on the biological function of sclerostin. The affected cysteine is the last cysteine residue of the cystine-knot motif and loss of this residue leads to retention of the mutant protein in the ER, possibly as a consequence of impaired folding. Together with a significant reduced ability to bind to LRP5 and inhibit Wnt signaling, the p.Cys167Arg mutation leads to a complete loss of function of sclerostin and thus to the characteristic sclerosteosis phenotype. (C) 2010 Wiley-Liss, Inc. Show less
Smoking is a common risk factor for many diseases(1). We conducted genome-wide association meta-analyses for the number of cigarettes smoked per day (CPD) in smokers (n = 31,266) and smoking... Show moreSmoking is a common risk factor for many diseases(1). We conducted genome-wide association meta-analyses for the number of cigarettes smoked per day (CPD) in smokers (n = 31,266) and smoking initiation (n = 46,481) using samples from the ENGAGE Consortium. In a second stage, we tested selected SNPs with in silico replication in the Tobacco and Genetics (TAG) and Glaxo Smith Kline (Ox-GSK) consortia cohorts (n = 45,691 smokers) and assessed some of those in a third sample of European ancestry (n = 9,040). Variants in three genomic regions associated with CPD (P < 5 x 10(-8)), including previously identified SNPs at 15q25 represented by rs1051730[A] (effect size = 0.80 CPD, P = 2.4 x 10(-69)), and SNPs at 19q13 and 8p11, represented by rs4105144[C] (effect size = 0.39 CPD, P = 2.2 x 10(-12)) and rs6474412-T (effect size = 0.29 CPD, P = 1.4 x 10(-8)), respectively. Among the genes at the two newly associated loci are genes encoding nicotine-metabolizing enzymes (CYP2A6 and CYP2B6) and nicotinic acetylcholine receptor subunits (CHRNB3 and CHRNA6), all of which have been highlighted in previous studies of smoking and nicotine dependence2-4. Nominal associations with lung cancer were observed at both 8p11 (rs6474412[T], odds ratio (OR) = 1.09, P = 0.04) and 19q13 (rs4105144[C], OR = 1.12, P = 0.0006). Show less
